Cardiovascular events in patients with COPD: TORCH study results

Abstract

Previous studies have suggested that long-term use of beta agonists to treat chronic obstructive pulmonary disease (COPD) may increase the risk of cardiovascular adverse events. In this post hoc analysis, data from the TOwards a Revolution in COPD Health (TORCH) study were used to investigate whether use of the long-acting beta(2) agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD.
TORCH was a randomised, double-blind, placebo controlled study conducted at 444 centres in 42 countries. Patients (n=6184; safety population) received twice daily combined salmeterol 50 microg plus fluticasone propionate 500 microg (SFC), either component alone, or placebo. Adverse events were recorded every 12 weeks for 3 years.
The probability of having a cardiovascular adverse event by 3 years was 24.2% for placebo, 22.7% for salmeterol, 24.3% for fluticasone propionate and 20.8% for SFC. Although a history of myocardial infarction doubled the probability of cardiovascular adverse events, the event rates remained similar across treatment groups.
Post hoc analysis of the 3-year TORCH dataset showed that salmeterol alone or in combination (SFC) did not increase the risk of cardiovascular events in patients with moderate to severe COPD.

Full text

Cardiovascular events in patients with COPD: TORCH
Study results
Peter M A Calverley,
1
Julie A Anderson,
2
Bartolome Celli,
3
Gary T Ferguson,
4
Christine Jenkins,
5
Paul W Jones,
6
Courtney Crim,
7
Lisa R Willits,
2
Julie C Yates,
7
Jørgen Vestbo,
8
on behalf of the TORCH Investigators
ABSTRACT
Background Previous studies have suggested that long-
term use of
b
agonists to treat chronic obstructive
pulmonary disease (COPD) may increase the risk of
cardiovascular adverse events. In this post hoc analysis,
data from the TOwards a Revolution in COPD Health
(TORCH) study were used to investigate whether use of
the long-acting
b
2
agonist salmeterol over 3 years
increased the risk of cardiovascular adverse events in
patients with moderate to severe COPD.
Methods TORCH was a randomised, double-blind,
placebo controlled study conducted at 444 centres in 42
countries. Patients (n¼6184; safety population) received
twice daily combined salmeterol 50
m
g plus fluticasone
propionate 500
m
g (SFC), either component alone, or
placebo. Adverse events were recorded every 12 weeks
for 3 years.
Results The probability of having a cardiovascular
adverse event by 3 years was 24.2% for placebo, 22.7%
for salmeterol, 24.3% for fluticasone propionate and
20.8% for SFC. Although a history of myocardial
infarction doubled the probability of cardiovascular
adverse events, the event rates remained similar across
treatment groups.
Conclusion Post hoc analysis of the 3-year TORCH
dataset showed that salmeterol alone or in combination
(SFC) did not increase the risk of cardiovascular events in
patients with moderate to severe COPD.
Chronic obstructive pulmonary disease (COPD) is
now recognised as being a highly prevalent condi-
tion
1
that causes significant morbidity and
mortality,
2
and commonly coexists with cardiovas-
cular disease.
3
Cardiovascular events are one of the
leading causes of mortality and hospitalisation in
patients with COPD, particularly in those with mild
to moderate disease.
45
Moreover, COPD is a strong
risk factor for cardiovascular events, independent of
smoking,
367
and impaired lung function is an
important marker for cardiovascular mortality.
89
However, it is unclear whether COPD interventions
other than smoking cessation
4
can modify the
increased cardiovascular risk associated with COPD.
Recently there has been concern that the long-
term use of inhaled bronchodilators commonly
used in the treatment of COPD, including long-
acting
b
2
agonist (LABA) and anticholinergic drugs,
may increase the risk of cardiovascular
complications.
10e14
However, prospective data
about the relative risk of therapy in patients with
sufficient symptoms to be offered treatment with
these drugs has, until recently, been lacking.
While the 3-year TOwards a Revolution in
COPD Health (TORCH) study primarily
investigated the effect of combination therapy with
the LABA salmeterol (SAL) and the inhaled corti-
costeroid fluticasone propionate (FP) compared
with placebo on all-cause mortality, other efficacy
outcomes and adverse events (AEs) were also
measured. The primary paper including the
mortality analysis has already been published.
15
It
reported that long-term use of SAL or the SAL plus
FP combination (SFC) did not increase the rate of
cardiac death. In view of the continuing concerns
about cardiovascular safety in COPD therapy, we
extended this analysis (post hoc) to consider the
occurrence of cardiovascular AEs and serious
adverse events (SAEs) in the TORCH study. We
also explored the factors that might determine the
incidence of cardiovascular events in these patients.
Some of these results have previously been
presented in abstract form.
16
METHODS
Patients
Details of patient eligibility and study entry criteria
have been published previously.
15
Eligible patients
were current or former smokers aged 40e80 years
with a prebronchodilator forced expiratory volume
in 1 s (FEV
1
)<60% of the predicted value and
a ratio of prebronchodilator FEV
1
to forced vital
capacity (FVC) of #0.70. The only exclusion
criterion with respect to comorbidities was that
subjects were considered unlikely to die of some-
thing other than COPD in the subsequent 3 years.
Design overview
The study design has been described in detail
previously.
15 17
TORCH was a multicentre, rand-
omised, double-blind, parallel-group, placebo
controlled study conducted at 444 centres in 42
countries. After a 2-week run-in period, eligible
patients were stratified by smoking status and
randomised to receive either SFC 50/500
m
g, SAL
50
m
g, FP 500
m
g or placebo twice daily for 3 years
via a Diskus/Accuhaler inhaler (GlaxoSmithKline,
Greenford, UK). Full details of the randomisation
procedure have been reported elsewhere.
15 17
The primary efficacy end point of the TORCH
study was all-cause mortality. Other end points
were rate of COPD exacerbations, health-related
quality of life, lung function and AEs. After
randomisation, patient visits occurred every
12 weeks to record any AE. At each visit the subject
was allowed to spontaneously mention any
<Supplementary tables are
published online only. To view
these files please visit the
journal online (http://thorax.bmj.
com).
1
University Hospital Aintree,
Liverpool, UK
2
GlaxoSmithKline, Middlesex,
UK
3
Caritas-St Elizabeth’s Medical
Center, Brighton,
Massachusetts, USA
4
Pulmonary Research Institute
of Southeast Michigan, Livonia,
Michigan, USA
5
Woolcock Institute of Medical
Research, NSW, Australia
6
University of London, London,
UK
7
GlaxoSmithKline, Research
Triangle Park, North Carolina,
USA
8
Hvidovre Hospital, Hvidovre,
Denmark and Wythenshawe
Hospital, Manchester, UK
Correspondence to
Professor P M A Calverley,
Department of Medicine,
University Hospital Aintree,
Longmoor Lane, Liverpool
L9 7AL, UK;
pmacal@liverpool.ac.uk
Received 28 January 2010
Accepted 19 April 2010
Thorax 2010;65:719e725. doi:10.1136/thx.2010.136077 719
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problems, then the investigator asked the following standard
questions: (1) ‘Have you had any (other) medical problems since
your last visit/assessment?’and (2) ‘Have you taken any new
medicines other than those given to you within this study since
your last visit/assessment?’An AE was defined as any unfav-
ourable and unintended sign (including a clinically significant
abnormal laboratory finding), symptom or disease temporally
associated with the use of the blinded study product, whether or
not it was considered to be related to that product.
SAEs were those that resulted in any of the following
outcomes: (1) death; (2) an immediate risk of death; (3) hospi-
talisation or prolongation of an existing hospitalisation; or (4)
any other important medical event which, in the opinion of the
investigator, jeopardised the subject’s health. An independent
safety and efficacy data monitoring committee performed safety
reviews of all SAEs every 6 months. Causes of death were
independently adjudicated in a standardised fashion by a clinical
end point committee.
18
Cardiovascular safety evaluation
Cardiovascular AEs were classified based on the Medical
Dictionary for Regulatory Activities (MedDRA) Version 8.1
terms. MedDRA is the AE classification dictionary endorsed by
the International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use (ICH). All events in the cardiac disorders system organ class
plus selected events from the vascular disorders and nervous
system disorders system organ classes were included (table 1).
Further analysis was also conducted on the subset of ischaemic
events and on events related to stroke (table 1). No specific
information was collected about whether patient-reported AEs
had been objectively verified.
Subjects receiving medications commonly used to treat
cardiovascular disease were identified; these medications were
selected from dictionary groupings (listed in table 1).
Statistical analysis
The study was powered for its primary all-cause mortality end
point and was not formally powered to detect differences in
numbers of AEs between treatments.
The safety population included all patients who took at least
one dose of study medication. The number and proportion of
patients reporting a cardiovascular AE over the 3 years were
summarised by treatment group. To correct for differential
treatment exposure between the treatments, the rate of cardiac
events per 1000 treatment years was calculated by dividing the
total number of AEs by the total number of years patients were
exposed to study treatment, then multiplying by 1000. On-
treatment deaths were defined as any death occurring up to
14 days after patients stopped their study medication.
The time to first cardiovascular AE was compared between
treatment groups using KaplaneMeier estimates and the log-
rank test, stratified by smoking status; KaplaneMeier cumula-
tive incidence curves were also generated. Statistical significance
was set at p<0.05.
RESULTS
Study population
Of 8554 patients with COPD recruited, 6184 were randomised
and evaluated for safety (figure 1). This included 72 patients
from five sites excluded from the published efficacy analyses.
15
One subject was randomised to placebo but took FP for the
majority of the treatment period and was analysed with the FP
group.
Demographic and baseline patient characteristics were
balanced across treatment groups (table 2). The mean age was
65 years, 76% were male, mean smoking history was 48 pack-
years and baseline postbronchodilator FEV
1
was 44% of
predicted. At baseline, 7% of patients reported a history of
previous myocardial infarction (MI), 41% were taking cardio-
vascular medications and 60% were taking short-acting anti-
cholinergic drugs. Use of the long-acting anticholinergic
tiotropium bromide during the study was low (3%) and was
similar across treatment groups. Of the 187 subjects receiving
tiotropium, over half took it for 12 weeks or less.
The proportion of patients who withdrew from the study was
highest in the placebo group (44%) and lowest in the SFC group
(34%) (SAL 37%, FP 39%). The total number of patient-years of
exposure to the study drugs was 3278 for placebo, 3531 for SAL,
3555 for FP and 3700 for SFC.
Cardiovascular AEs
The proportion of patients who experienced a cardiovascular AE
or cardiovascular SAE during the study was similar across
treatment groups (17e20% and 10e12%, respectively) (table 3).
When expressed as the number of events per 1000 treatment
years, the rate of cardiovascular AEs was 142 in the placebo
group and 110 in the SFC group. The probability of patients
having a cardiovascular AE by 3 years was lowest for SFC
at 20.8% (24.2% for placebo, 22.7% for SAL and 24.3% for FP;
figure 2A; table 3). The probability of patients having a cardio-
vascular SAE by 3 years was lowest for SFC at 12.5% (15.4% for
placebo, 13.6% for SAL and 14.7% for FP; table 3).
The proportion of patients experiencing an ischaemic cardio-
vascular AE was similar across treatment groups (9e11%;
table 4). The rate of ischaemic cardiovascular AEs per 1000
treatment years was 68 for placebo, 70 for SAL, 62 for FP and 54
for SFC. The probability of patients having an ischaemic cardio-
vascular AE by 3 years was lowest for SFC at 11.3%, 14.6% for
placebo, 13.4% for SAL and 13.8% for FP (figure 2B and table 4).
The proportion of patients with a stroke-related AE over
the 3-year course of the study was similar in each treatment
group (3% placebo, 2% SAL, 3% FP and 3% SFC). The rate of
Table 1 List of MedDRA system organ class (SOC) high-level group
terms (HLGT) used for analysis of cardiovascular events, ischaemic
cardiovascular events and stroke events, and list of cardiovascular
medications included in the analysis
Cardiovascular events
<Cardiac disorders (SOC)
– Coronary artery disorders
– Cardiac arrhythmias
– Heart failures
– Cardiac disorder signs and symptoms
– Myocardial disorders
– Cardiac valve disorders
– Pericardial disorders
<Nervous system disorders (SOC)
– Central nervous system vascular disorders
<Vascular disorders (SOC)
– Arteriosclerosis, stenosis, vascular
insufficiency and necrosis
– Aneurysms and artery dissections
– Embolism and thrombosis
Ischaemic events
<Ischaemic coronary artery
disorders
<Coronary artery disorders NEC
<Heart failures NEC
<Right ventricular failures
<Left ventricular failures
<Cardiomyopathies
<Pericardial disorders NEC
<Non-infectious pericarditis
Stroke events
<Central nervous system
vascular disorders (HLGT)
Cardiovascular medications
<ACE inhibitors
<Angiotensin II antagonists
<Antihypertensives
<Beta blockers
<Calcium channel blockers
<Antiarrythmics
<Cardiac glycosides
<Adrenergic and dopaminergic
agents
<Organic nitrates
NEC, not elsewhere classified.
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stroke-related AEs per 1000 treatment years was 17 for placebo,
13 for SAL, 16 for FP and 12 for SFC.
The likelihood of experiencing a cardiovascular AE was unaf-
fected by gender and current smoking status (table 5). Patients
who were on cardiovascular medications at baseline (figure 3),
reported a previous MI (figure 4), were older or had lower
baseline FEV
1
(table 5) had a higher probability of having
a cardiovascular AE. There were no significant differences
between treatments in the likelihood of an event being reported,
nor was there consistent evidence for an interaction between
treatment and spirometrically-defined disease severity with
respect to cardiac events (see table 1 in online supplement) . In
patients who had previously had an MI, the likelihood of having
a cardiovascular event over 3 years was 54.4% on salmeterol
compared with 49.1% with placebo (p ¼0.51) and 44.1% with
SFC (p¼0.051 relative to salmeterol (figure 4B and table 5).
Figure 1 Patient flow. *The number of
patients who underwent randomisation
and the number of those included in the
safety population differ in the placebo
group and the fluticasone propionate
group because one patient who was
assigned to placebo received
fluticasone propionate for more than
half the study period; this patient was
therefore included in the fluticasone
propionate group for the safety
analysis. AE, adverse event.
Table 2 Patient demographic and baseline characteristics of the safety population
Variable
Placebo
(n[1544)
Salmeterol
(n [1542)
FP
(n [1552)
SFC
(n [1546)
Age at enrolment, years 65.1 (8.1) 65.2 (8.2) 65.1 (8.4) 65.0 (8.3)
Male gender, n (%) 1175 (76) 1176 (76) 1169 (75) 1164 (75)
Body mass index, kg/m
2
25.5 (5.2) 25.4 (5.2) 25.3 (5.1) 25.4 (5.3)
Postbronchodilator FEV
1
, % predicted 44.1 (12.2) 43.6 (12.6) 44.1 (12.3) 44.3 (12.4)
<30%, n (%) 215 (14) 261 (17) 223 (14) 246 (16)
30e<50%, n (%) 786 (51) 750 (49) 785 (51) 735 (48)
$50%, n (%) 543 (35) 531 (34) 544 (35) 565 (37)
Geographical region, n (%)
USA 348 (23) 351 (23) 350 (23) 352 (23)
Asia Pacific 188 (12) 189 (12) 193 (12) 188 (12)
Eastern Europe 297 (19) 296 (19) 293 (19) 293 (19)
Western Europe 478 (31) 475 (31) 481 (31) 477 (31)
Other 234 (15) 231 (15) 234 (15) 236 (15)
Current smoker, n (%) 664 (43) 657 (43) 666 (43) 667 (43)
Pack-years smoked 48.6 (27.0) 49.3 (27.7) 49.2 (28.5) 46.9 (26.5)
Previous COPD treatment, n (%)*
ICS alone 346 (22) 278 (18) 310 (20) 295 (19)
LABA alone 118 (8) 138 (9) 133 (9) 137 (9)
ICS + LABA 453 (29) 417 (27) 416 (27) 437 (28)
Neither ICS nor LABA 557 (36) 634 (41) 629 (41) 623 (40)
Previous MI, n (%) n¼1543 n¼1541 n¼1552 n¼1545
0 1432 (93) 1427 (93) 1460 (94) 1443 (93)
1 91 (6) 93 (6) 79 (5) 83 (5)
$2 29 (1) 21 (1) 13 (<1) 19 (1)
Baseline CV treatment, n (%)y608 (39%) 630 (41%) 630 (41%) 662 (43%)
Baseline short-acting anticholinergics, n (%) 926 (60%) 921 (60%) 943 (61%) 925 (60%)
Data are mean (SD) unless otherwise indicated.
CV, cardiovascular; FEV
1
, forced expiratory volume in 1 s; FP, fluticasone propionate; ICS, inhaled corticosteroid; LABA, long-acting
b
2
agonist; MI, myocardial infarction; SFC, salmeterol/fluticasone propionate combination.
*Self-reported in the 12 months prior to screening.
ySee list in table 1.
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However, the pattern of risk in other groups was inconsistent
with salmeterol-treated patients having a similar incidence of
events to patients treated with FP, as identified by their use of
previous cardiac therapies (figure 3B). Patients who were taking
short-acting anticholinergic treatment at baseline had a higher
probability of cardiovascular events (table 5); however, these
patients also had lower baseline percentage predicted FEV
1
. The
pattern of cardiovascular events was similar across treatment
groups irrespective of baseline anticholinergic use.
Cardiovascular deaths
There were 882 deaths (14%) during the 3-year study period,
including those both on and off study treatment (see table 2 in
online supplement). Of these, 239 were due to cardiovascular
causes as adjudicated by the clinical end point committee. For
placebo, 71 deaths (4.6%) were due to cardiovascular causes
compared with 45 (2.9%) for SAL, 61 (3.9%) for FP and 62 (4.0%)
for SFC. There were 468 deaths while on treatment, of which
172 were due to cardiovascular causes. For placebo, 47 (3.0%)
deaths were due to cardiovascular causes compared with 33
(2.1%) for SAL, 43 (2.8%) for FP and 49 (3.2%) for SFC.
DISCUSSION
COPD is not simply a lung disease
19
but is associated with an
increased likelihood of complications outside the lungs. Support
for this concept comes from recent studies that have shown
significantly increased pulse wave velocity, independent of
smoking status and other risk factors, in patients with stable
COPD.
20
In these circumstances it is no surprise that cardio-
vascular morbidity and mortality is high in COPD.
Both
b
agonists and antimuscarinic agents, the main classes of
bronchodilator drugs used to treat COPD, have the potential to
precipitate cardiac rhythm disturbances and other cardiac
events; however, this has not been regarded as important in
clinical practice until recently. Unfortunately, unlike the situa-
tion for cardiovascular disease, most studies of drug treatment in
COPD have been relatively brief (#1 year) and have only
reported on-treatment data. These studies have made the largest
contribution to the systematic reviews in this field, at least as far
as patients receiving treatment for symptoms are concerned. As
the TORCH study was conducted in a patient group likely to be
prescribed inhaled LABAs, the TORCH dataset addresses some
of the problems inherent in these earlier analyses. The current
analysis provides generally reassuring results about the cardio-
vascular safety of inhaled LABA treatments in patients with
COPD.
TORCH is the largest and longest prospective trial to examine
the role of an inhaled LABA and an inhaled corticosteroid in
COPD. Half of the >6000 patients were randomised to a regime
containing SAL and, allowing for dropouts, this provides 7231
patient-years of exposure to these agents. Over the 3 years,
approximately 1 in 5 patients experienced a cardiovascular AE.
The event rate was lowest in those receiving SAL in combination
with FP and not different from those patients treated with
placebo or with LABA monotherapy. A SAE requiring hospital-
isation and new cardiovascular ischaemic events were approxi-
mately half as common as the total cardiovascular event rate,
Figure 2 Cumulative incidence of (A) all cardiovascular adverse events
and (B) ischaemic cardiovascular adverse events. Full details of the data
presented in (A) and (B) including statistical testing are shown in tables
3 and 4, respectively. Vertical bars represent standard errors. AE,
adverse event; FP, fluticasone propionate; SAL, salmeterol; SFC,
salmeterol/fluticasone propionate combination.
Table 3 Summary of all cardiovascular AEs and SAEs
Placebo
(n[1544)
Salmeterol
(n[1542)
FP
(n[1552)
SFC
(n[1546)
All CV AEs
Patients with CV AE, n (%) 281 (18) 287 (19) 306 (20) 267 (17)
Rate* of CV AE (no of events) 142 (466) 141 (496) 130 (462) 110 (405)
Probabilityyof CV AE by
3 years, %
24.2 22.7 24.3 20.8
Hazard ratio 95% CI p Value
SFC vs placebo 0.83 0.70 to 0.98 0.031
Salmeterol vs placebo 0.96 0.82 to 1.13 0.629
FP vs placebo 1.00 0.85 to 1.18 0.994
CV SAEs
Patients with CV SAE, n (%) 176 (11) 168 (11) 180 (12) 160 (10)
Rate* of CV SAE (no of events) 75 (245) 66 (234) 66 (236) 57 (209)
Probabilityyof CV SAE by
3 years, %
15.4 13.6 14.7 12.5
Hazard ratio 95% CI p Value
SFC vs placebo 0.81 0.65 to 1.00 0.046
SAL vs placebo 0.89 0.72 to 1.10 0.268
FP vs placebo 0.94 0.76 to 1.15 0.542
*Rate¼number of events per 1000 treatment years.
yKaplaneMeier probability.
AEs, adverse events; CV, cardiovascular; FP, fluticasone propionate; SAEs, serious adverse
events; SFC, salmeterol/fluticasone propionate combination.
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but there was a similar pattern across treatment groups. Seven
percent of patients had a history of previous MI. In this group
the cardiovascular event rate, as would be expected, was higher.
Again, no trend was seen for more AEs in those patients rand-
omised to treatment with SAL in combination with FP.
However, the data for SAL alone are inconclusive, possibly due
to the small sample size in this smaller subgroup of patients.
Unlike other COPD studies, TORCH developed a rigorous
methodology for determining the likely cause of death which
was adjudicated by an expert panel blinded to the study medi-
cation.
18
Moreover, there was effectively complete follow-up of
the vital status of all patients 3 years after randomisation. In
this data set, the patients randomised to LABA alone had the
lowest rate of cardiovascular death while those who received
placebo had the largest number of events. The number of on-
treatment deaths, analogous to data included in earlier COPD
studies, showed a similar pattern across treatments.
A range of predictable factors increases the cardiovascular event
rate including higher age, a history of previous cardiac disease and
worse lung function. None of these factors interacted with
treatment to identify a specific‘at-risk’group. Somewhat
surprisingly we saw no difference in event rate between current
and ex-smokers, which may reflect our study entry criteria or
possibly the nature of cardiovascular disease in patients with
COPD. We did not control for the use of inhaled anticholinergic
drugs although, when used, this was predominantly ipratropium
as tiotropium was not available in most countries until
TORCH was nearing completion. In those patients treated with
an anticholinergic agent, there was a suggestion of a somewhat
higher cardiovascular event rate but these patients also had lower
baseline lung function. The association seen is therefore likely to
represent the confounding influence of disease severity, an issue
that has made interpretation of previous studies of COPD
therapy particularly difficult. Patients in GOLD stage 4 receiving
salmeterol appeared to have more cardiac events, although the
Table 5 KaplaneMeier probability of a cardiovascular adverse event
by 3 years by subgroups
N
Placebo
(n[1544)
Salmeterol
(n[1542)
FP
(n[1552)
SFC
(n[546)
Age
<55 706 13.2 12.5 13.4 13.4
55e64 1988 20.2 18.8 20.7 17.4
65e74 2706 26.6 24.8 26.9 22.1
$75 784 39.2 34.9 35.4 32.9
Sex
Male 4684 24.4 23.0 24.0 20.7*
Female 1500 23.4 21.9 25.3 21.0
Smoking status
Current 2654 22.2 22.0 22.4 20.5
Former 3530 25.8 23.3 25.9 20.9*
Baseline FEV
1
<30% 945 25.8 32.1 26.7 23.5
30e<50% 3056 25.7 20.7 25.4 23.4
$50% 2183 21.7 21.7 21.8 16.2*
Baseline CV treatment
Yes 2530 33.5 30.3 30.4 27.9*
No 3654 18.3 17.6 20.2 15.4
Prior MI
Yes 419 49.1 54.4 41.0 44.1
No 5762 22.2 20.2 23.3 19.1
Baseline short-acting anticholinergics
Yes 3715 25.2 24.0 25.6 22.0
No 2469 22.7 21.0 22.4 18.9
*p<0.05 versus placebo.
CV, cardiovascular; FEV
1
, forced expiratory volume in 1 s; FP, fluticasone propionate;
MI, myocardial infarction; SFC, salmeterol/fluticasone propionate combination.
Table 4 Ischaemic cardiovascular AEs
Placebo
(n [1544)
Salmeterol
(n [1542)
FP
(n [1552)
SFC
(n [1546)
Patients with ischaemic
CV AE, n (%)
166 (11) 166 (11) 167 (11) 144 (9)
Rate* of ischaemic CV AE
(no of events)
68 (224) 70 (240) 62 (222) 54 (199)
Probabilityyof ischaemic
CV AE by 3 years, %
14.6 13.4 13.8 11.3
Hazard ratio 95% CI p Value
SFC vs placebo 0.76 0.61 to 0.95 0.016
Salmeterol vs
placebo
0.93 0.75 to 1.16 0.531
FP vs placebo 0.93 0.75 to 1.15 0.477
*Rate¼number of events per 1000 treatment years.
yKaplaneMeier probability.
AEs, adverse events; CV, cardiovascular; FP, fluticasone propionate;
SFC, salmeterol/fluticasone propionate combination.
Figure 3 Cumulative incidence of all cardiovascular adverse events in
patients who (A) did not receive or (B) did receive cardiovascular
medication (listed in table 1) in the 12 months prior to screening. Full
details of the data presented in this figure including statistical testing are
shown in table 5. Vertical bars represent standard errors. AE, adverse
event; CV, cardiovascular; FP, fluticasone propionate; SAL, salmeterol;
SFC, salmeterol/fluticasone propionate combination.
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differences between treatment groups were not significant. This
finding is at odds with the lower than average reported incidence
of events with salmeterol in GOLD stage 3 and probably reflects
the lower sample size in the GOLD stage 4 population with
correspondingly widened confidence intervals for these data.
Our study has strengths and some limitations. We monitored
our patients regularly throughout the 3-year study, but events
were self-reported rather than being in response to a prede-
termined diagnostic list. We did not undertake ECG or echo-
cardiographic evaluations at the study outset and there was no
requirement to provide objective documentation of the nature of
any new cardiovascular episode. However, we did include
patients with a history of cardiovascular disease provided it was
not thought that this was the main cause for their symptoms or
that they were likely to die from this during the study. This is an
important difference from earlier studies where more restrictive
eligibility criteria were applied. As in other large COPD studies,
for example UPLIFT
21
and TRISTAN,
22
patients randomised to
placebo tended to withdraw more frequently than those rand-
omised to active therapy, probably reflecting their deteriorating
condition. Thus, patients continuing in the placebo arm of our
on-treatment analysis represent a relatively fitter group of
patients with COPD. Despite this, we saw no suggestion that
patients on treatment were more likely to experience adverse
cardiovascular problems. Finally, we lack data about whether the
use of these agents increases the risk of cardiovascular events
during an acute exacerbation. Recent literature reviews have
failed to report any association between use of high-dose
b
agonists and risk of arrhythmias in this setting.
23
For some of our data the SFC combination appeared to be
associated with important reductions in the incidence of adverse
cardiovascular events. Although this difference may simply have
been due to chance, other biologically plausible mechanisms
exist which can account for this effect. It has been suggested
that inflammation occurring in COPD might directly promote
vascular damage
24
and this may be reduced when airway
inflammation is decreased, as has been demonstrated with
a LABA/inhaled steroid combination.
25
Our data cannot address
this hypothesis, but this concept is supported by recent obser-
vations from a large database study that patients who used
inhaled corticosteroids were less likely to experience cardiovas-
cular deaths than those who received bronchodilators alone.
12
This is consistent with the general conclusions of the TORCH
study that there was a reasonable (but not conclusive proba-
bility that combination treatment with SAL plus FP prolongs
life in COPD. An alternative explanation for the effect of SFC on
cardiovascular outcomes may be its relative efficiency in
preventing exacerbations of COPD which are associated with
elevations in troponin T and a raised cardiac infarction injury
score, at least in hospitalised patients.
26 27
Further studies will
be needed to address whether these potentially important
mechanisms best explain the observed data.
In summary, in this large prospectively collected dataset, the
occurrence of new cardiovascular AEs was no more frequent in
patients treated with a LABA than in those treated with placebo.
In addition, we saw some evidence that the combination of
a LABA and an inhaled corticosteroid might offer a degree of
cardioprotection. These data from patients with moderate to
severe COPD provide reassurance that our current use of inhaled
LABA therapies is not harmful to cardiovascular health.
Acknowledgements The authors acknowledge medical writing support from David
Cutler, a professional medical writer with Gardiner-Caldwell Communications, in the
preparation of this manuscript; this support was funded by GlaxoSmithKline.
Funding This work was supported by GlaxoSmithKline.
Competing interests PMAC has received consulting fees from AstraZeneca,
GlaxoSmithKline, Nycomed and Pfizer; speaking fees from GlaxoSmithKline and
Nycomed; and grant support from Boehringer-Ingelheim and GlaxoSmithKline. JAA,
CC, LRW and JCY are employed by and hold stock in GlaxoSmithKline. BC has
received consulting fees from Altana, AstraZeneca, Boehringer-Ingelheim and
GlaxoSmithKline; speaking fees from Altana, AstraZeneca, Boehringer-Ingelheim and
GlaxoSmithKline; and grant support from Boehringer-Ingelheim and GlaxoSmithKline.
GTF has received consulting fees from Boehringer-Ingelheim, GlaxoSmithKline,
Novartis and Schering Plough; speaking fees from Boehringer-Ingelheim,
GlaxoSmithKline and Pfizer; and grant support from Altana, Boehringer-Ingelheim,
Emphasys Medical Inc, Forrest, GlaxoSmithKline, Mannkind Corporation and Novartis.
CJ has received consulting fees from Altana, AstraZeneca, Boehringer-Ingelheim and
GlaxoSmithKline; speaking fees from Altana, AstraZeneca, Boehringer-Ingelheim,
GlaxoSmithKline and Novartis; and grant support from GlaxoSmithKline. PWJ has
received consulting fees from AstraZeneca, GlaxoSmithKline, Novartis and Roche;
speaking fees from AstraZeneca and GlaxoSmithKline; and grant support from
Boehringer-Ingelheim and GlaxoSmithKline. JV has received consulting fees from
AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Hoffman-LaRoche and
Nycomed; speaking fees from AstraZeneca, Boehringer-Ingelheim and
GlaxoSmithKline; and grant support from GlaxoSmithKline.
Ethics approval The study was approved by local ethics review committees and was
conducted in accordance with the Declaration of Helsinki and Good Clinical Practice
guidelines. All patients gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Figure 4 Cumulative incidence of all cardiovascular adverse events in
patients who (A) had not experienced or (B) had experienced
a myocardial infarction prior to study entry. Full details of the data
presented in this figure including statistical testing are shown in table 5.
Vertical bars represent standard errors. AE, adverse event; FP,
fluticasone propionate; MI, myocardial infarction; SAL, salmeterol;
SFC, salmeterol/fluticasone propionate combination.
724 Thorax 2010;65:719e725. doi:10.1136/thx.2010.136077
Chronic obstructive pulmonary disease
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Thorax 2010;65:719e725. doi:10.1136/thx.2010.136077 725
Chronic obstructive pulmonary disease
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TORCH Study results
Cardiovascular events in patients with COPD:
Julie C Yates and Jørgen Vestbo Willits,Ferguson, Christine Jenkins, Paul W Jones, Courtney Crim, Lisa R
Peter M A Calverley, Julie A Anderson, Bartolome Celli, Gary T
doi: 10.1136/thx.2010.136077
2010 65: 719-725 Thorax
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